Membranous GlomerulonephritisPhase 2NCT00050713
Sirolimus Therapy for Idiopathic and Lupus Membranous Nephropathy
A Phase 2 study testing Sirolimus in people with Membranous Glomerulonephritis and Lupus Membranous Nepropathy, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
Trial summary
This study will evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in reducing the amount of protein in the urine in patients with membranous nephropathy. Read more about this study
- Who is it for?
- Ages 13 years and older
- Conditions the study is for
- Membranous Glomerulonephritis, Lupus Membranous Nepropathy
- What is being tested?
- Sirolimus
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Dec 2002to 27 Aug 2007
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Ability and willingness to provide informed consent (adults greater than or equal to 18 years) or assent (children greater than or equal to 13 years) to all aspects of the study after full information is provided.
- Nephrotic range proteinuria that persists for at least 3 months.
- Nephrotic range proteinuria that persists despite angiotensin antagonist therapy (ACE inhibitor or ARB) for at least on month, unless intolerant. If patients have not started ACE inhibitor therapy before they are referred to NIH, we plan to start lisinopril 5 mg daily. We will advance the dose of ACE inhibitor as tolerated. Nephrotic range proteinuria, defined as 24 hour urine protein excretion greater than or equal to 3.5 g/d, must be documented in at least two 24 hour urine collections obtained during the month prior to initiating sirolimus. Incomplete urine collections (based on inadequate creatinine excretion) will be excluded.
- Renal biopsy must reveal typical changes of membranous nephropathy by light and electron microscopy.
- SLE as defined by the presence of at least 4 criteria established by the American Rheumatism Association (Lupus Membranous Nephropathy) or no evidence of a secondary form of membranous nephropathy (Idiopathic Membranous Nephropathy).
Who cannot join
- Intolerance to sirolimus or prior use of sirolimus for membranous nephropathy.
- Estimated GFR less than 30 mL/min/1.73(2) (determined by the 5 variable version of the MDRD Study prediction equation).
- Immunosuppressive medications or experimental medications of any type during the two-month period prior to initiating sirolimus, with the following two exceptions:
- First, patients with lupus membranous nephropathy are permitted to have received modest doses of corticosteroids (no more than the equivalent of prednisone 10mg/day) for control of extra-renal manifestations of SLE during the two-month period prior to starting sirolimus treatment.
- Second, patients with worsening nephrotic syndrome (urine protein excretion rate doubles +/or serum albumin decreases by greater than or equal to 1.0 g/ dL to less than 2.5 g/dL on at least 2 determinations during or following a previous immunosuppressive treatment) should fulfill the following criteria:
- should be off prednisone for at least 2 weeks before performing the baseline evaluation and starting sirolimus (if the patient has idiopathic membranous nephropathy): b) should be on low-dose corticosteroids (no more than the equivalent of prednisone 10 mg/day) for at least 2 weeks before performing the baseline evaluation and starting sirolimus (if the patient lupus membranous nephropathy); c) should be off cyclosporine for at least 2 weeks before performing the baseline evaluation and starting sirolimus; d) should be off cyclophosphamide, chlorambucil, azathioprine and mycophenolate mofetil for at least 4 weeks before performing the baseline evaluation and starting sirolimus;
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- Children less than 13.0 years.
- Active acute or chronic infection requiring antimicrobial therapy or serious viral infection (e.g. HIV, hepatitis, herpes zoster). Patients with a reactive PPD must have completed a 6 to 12 month course of isoniazid as recommended by an infectious disease consultant. Patients with a non-reactive PPD and non-reactive anergy panel must complete a 6 to 12 month course of isoniazid if recommended by an infectious disease consultant.
- Pregnant women, nursing mothers or individuals (men and women) not practicing birth control.
- Uncontrolled hypertension, defined as BP greater than 140/90 on greater than 25% of measurements. Blood pressures will be measured 3 times at each clinic visit after the patient has sat quietly for at least 5 minutes. Thus at least 6 BP determinations will be recorded prior to initiating sirolimus therapy.
- Chronic liver disease sufficiently severe to impair sirolimus metabolism; this would include prolonged pro-thrombin time. Patients with abnormal liver function tests will be evaluated by the Hepatology Consult Service to determine whether protocol participation is appropriate.
- Basal thrombocytopenia less than 100,000 cells/microliters or absolute neutrophil count less than 2000 cells/microliters or hematocrit less than 30.
- Cancer diagnosis or cancer recurrence within the preceding 5 years, excluding basal cell carcinoma of the skin.
- Routine use of NSAIDS, defined as NSAID use more than two doses a week.
- Clinically significant medical conditions, which in the opinion of the investigators, could increase the subject s risk of participating in the study or could confound the interpretation of the results of the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy
This study will evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in reducing the amount of protein in the urine in patients with membranous nephropathy. This condition involves damage to the walls of tiny blood vessel filters in the kidneys called glomeruli, which allows blood proteins to leak into the urine. Patients have low blood protein levels and high blood cholesterol. Some patients may have leg swelling, impaired kidney function, blood vessel and heart disease, and a risk of emboli (blood clots that travel to the lungs). Drugs currently used to treat membranous nephropathy vary in their effectiveness among patients and can cause severe side effects.
The Food and Drug Administration has approved sirolimus for suppressing the immune system of patients who have had a kidney transplant to reduce the risk of organ rejection. The drug does not have certain side effects that have caused problems for patients treated with other immunosuppressants, such as: prednisone (weight gain, round face, diabetes, weak and fractured bones, and cataracts); cyclophosphamide (fertility problems, bladder injury and bladder cancer, and other cancers); chlorambucil (fertility problems, seizures, acute leukemia, and other cancers); and cyclosporine (kidney toxicity, increased facial hair, and seizures).
Read more
Patients 13 years of age or older with idiopathic membranous nephropathy or lupus membranous nephropathy may be eligible for this study. Candidates must have completed at least one month of treatment with a stable dose of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). They will be screened with a medical history, physical examination, blood tests, skin test for exposure to tuberculosis, and an examination for infection, cancers, and other conditions that can cause membranous nephropathy.
Participants will take sirolimus once a day for 1 year, except for the first day of treatment, when they will take three doses to quickly bring their blood levels of the drug up to a therapeutic level. They will undergo evaluations at the NIH in Bethesda, Maryland, at baseline (before starting treatment) and again at 1- to 4-month intervals during the study. In addition, they will have blood tests every week for the first month and every 2 weeks for the second month; then blood and urine tests once a month for the next 10 months of treatment and then every 4 months for a 12-month period after treatment stops. These tests will evaluate drug side effects and the response to therapy, and will determine if the therapeutic benefits persist long-term when treatment stops.
Patients will also be asked to have optional kidney function tests during the baseline evaluation and at the end of the follow-up period to measure kidney filtration and blood flow rates. Those who participate will be given fluids and other substances by vein to accurately measure kidney function. They will then have blood and urine samples collected about four times over a 1-hour period after drinking fluids to increase urine output.
Patients who experience a substantial increase in proteinuria or substantial decrease in kidney function during the course of treatment will stop taking sirolimus and be taken off the study.
Read the detailed description
This is a phase 2 trial to evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in patients with idiopathic and lupus membranous nephropathy. Patients (age greater than or equal to 13 years) will be invited to participate if they have persistent nephrotic range proteinuria despite standard treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker for at least one month, unless intolerant. These individuals are at risk for renal function deterioration as well as cardiovascular and thrombo-embolic complications of the nephrotic syndrome. Renal function, the degree of proteinuria and side effects will be monitored closely throughout the study. Physiologic measures of glomerular function will be examined at study entry and at the conclusion of the trial.
- Being tested
- Sirolimus
- Keywords
- Kidney Disease, Glomerulonephritis, Lupus Nephritis, Nephrotic Syndrome, Hyperlipidemia
- Medical subject headings
- Glomerulonephritis, Membranous, Kidney Diseases, Glomerulonephritis, Lupus Nephritis, Nephrotic Syndrome, Hyperlipidemias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
The number of patients who are in 1) complete remission or 2) complete or partial remission.
Measured: 12 months after starting sirolimus
Secondary outcomes (2)
The number of patients who are in Complete or Partial Remission or Limited Response.
Measured: 12 months after starting sirolimus
Frequency of adverse effects
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Dec 2002 (estimated)
- Study start17 Dec 2002
- Primary completion27 Aug 2007
- Study completion27 Aug 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Membranous GlomerulonephritisStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- Howard A Austin, M.D., Principal investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00050713
- Sponsor's protocol ID
- 030071
- Other IDs
- 03-DK-0071
- Status last verified
- 7 Jul 2015
- First submitted
- 17 Dec 2002
- Last updated
- 6 Oct 2017
- Results posted
- No
Publications
Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol. 1995 Jul;6(1):35-47. doi: 10.1681/ASN.V6135.
PubMed 7579068Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis). J Am Soc Nephrol. 1996 Dec;7(12):2518-26. doi: 10.1681/ASN.V7122518.
PubMed 8989729McMillan JI, Riordan JW, Couser WG, Pollock AS, Lovett DH. Characterization of a glomerular epithelial cell metalloproteinase as matrix metalloproteinase-9 with enhanced expression in a model of membranous nephropathy. J Clin Invest. 1996 Feb 15;97(4):1094-101. doi: 10.1172/JCI118502.
PubMed 8613533
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy
- ClinicalTrials.gov ID
- NCT00050713
- Acronym / sponsor ID
- 030071
- Keywords
- Kidney Disease, Glomerulonephritis, Lupus Nephritis, Nephrotic Syndrome, Hyperlipidemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- 17 Dec 2002
- Primary completion
- 27 Aug 2007 (actual)
- Study completion
- 27 Aug 2007 (actual)
- First posted
- 18 Dec 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in reducing the amount of protein in the urine in patients with membranous nephropathy. This condition involves damage to the walls of tiny blood vessel filters in the kidneys called glomeruli, which allows blood proteins to leak into the urine. Patients have low blood protein levels and high blood cholesterol. Some patients may have leg swelling, impaired kidney function, blood vessel and heart disease, and a risk of emboli (blood clots that travel to the lungs). Drugs currently used to treat membranous nephropathy vary in their effectiveness among patients and can cause severe side effects.
The Food and Drug Administration has approved sirolimus for suppressing the immune system of patients who have had a kidney transplant to reduce the risk of organ rejection. The drug does not have certain side effects that have caused problems for patients treated with other immunosuppressants, such as: prednisone (weight gain, round face, diabetes, weak and fractured bones, and cataracts); cyclophosphamide (fertility problems, bladder injury and bladder cancer, and other cancers); chlorambucil (fertility problems, seizures, acute leukemia, and other cancers); and cyclosporine (kidney toxicity, increased facial hair, and seizures).
Patients 13 years of age or older with idiopathic membranous nephropathy or lupus membranous nephropathy may be eligible for this study. Candidates must have completed at least one month of treatment with a stable dose of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). They will be screened with a medical history, physical examination, blood tests, skin test for exposure to tuberculosis, and an examination for infection, cancers, and other conditions that can cause membranous nephropathy.
Participants will take sirolimus once a day for 1 year, except for the first day of treatment, when they will take three doses to quickly bring their blood levels of the drug up to a therapeutic level. They will undergo evaluations at the NIH in Bethesda, Maryland, at baseline (before starting treatment) and again at 1- to 4-month intervals during the study. In addition, they will have blood tests every week for the first month and every 2 weeks for the second month; then blood and urine tests once a month for the next 10 months of treatment and then every 4 months for a 12-month period after treatment stops. These tests will evaluate drug side effects and the response to therapy, and will determine if the therapeutic benefits persist long-term when treatment stops.
Patients will also be asked to have optional kidney function tests during the baseline evaluation and at the end of the follow-up period to measure kidney filtration and blood flow rates. Those who participate will be given fluids and other substances by vein to accurately measure kidney function. They will then have blood and urine samples collected about four times over a 1-hour period after drinking fluids to increase urine output.
Patients who experience a substantial increase in proteinuria or substantial decrease in kidney function during the course of treatment will stop taking sirolimus and be taken off the study.
Detailed description
This is a phase 2 trial to evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in patients with idiopathic and lupus membranous nephropathy. Patients (age greater than or equal to 13 years) will be invited to participate if they have persistent nephrotic range proteinuria despite standard treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker for at least one month, unless intolerant. These individuals are at risk for renal function deterioration as well as cardiovascular and thrombo-embolic complications of the nephrotic syndrome. Renal function, the degree of proteinuria and side effects will be monitored closely throughout the study. Physiologic measures of glomerular function will be examined at study entry and at the conclusion of the trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 13 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- Ability and willingness to provide informed consent (adults greater than or equal to 18 years) or assent (children greater than or equal to 13 years) to all aspects of the study after full information is provided.
- Nephrotic range proteinuria that persists for at least 3 months.
- Nephrotic range proteinuria that persists despite angiotensin antagonist therapy (ACE inhibitor or ARB) for at least on month, unless intolerant. If patients have not started ACE inhibitor therapy before they are referred to NIH, we plan to start lisinopril 5 mg daily. We will advance the dose of ACE inhibitor as tolerated. Nephrotic range proteinuria, defined as 24 hour urine protein excretion greater than or equal to 3.5 g/d, must be documented in at least two 24 hour urine collections obtained during the month prior to initiating sirolimus. Incomplete urine collections (based on inadequate creatinine excretion) will be excluded.
- Renal biopsy must reveal typical changes of membranous nephropathy by light and electron microscopy.
- SLE as defined by the presence of at least 4 criteria established by the American Rheumatism Association (Lupus Membranous Nephropathy) or no evidence of a secondary form of membranous nephropathy (Idiopathic Membranous Nephropathy).
Key exclusion criteria (15 listed)
- Intolerance to sirolimus or prior use of sirolimus for membranous nephropathy.
- Estimated GFR less than 30 mL/min/1.73(2) (determined by the 5 variable version of the MDRD Study prediction equation).
- Immunosuppressive medications or experimental medications of any type during the two-month period prior to initiating sirolimus, with the following two exceptions:
- First, patients with lupus membranous nephropathy are permitted to have received modest doses of corticosteroids (no more than the equivalent of prednisone 10mg/day) for control of extra-renal manifestations of SLE during the two-month period prior to starting sirolimus treatment.
- Second, patients with worsening nephrotic syndrome (urine protein excretion rate doubles +/or serum albumin decreases by greater than or equal to 1.0 g/ dL to less than 2.5 g/dL on at least 2 determinations during or following a previous immunosuppressive treatment) should fulfill the following criteria:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sirolimus | Drug | – |
Primary outcome
The number of patients who are in 1) complete remission or 2) complete or partial remission.
Time frame: 12 months after starting sirolimus
2 secondary outcomes
The number of patients who are in Complete or Partial Remission or Limited Response.
Time frame: 12 months after starting sirolimus
Frequency of adverse effects
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2017.
- Background: PubMed 7579068Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol. 1995 Jul;6(1):35-47. doi: 10.1681/ASN.V6135.
- Background: PubMed 8989729Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis). J Am Soc Nephrol. 1996 Dec;7(12):2518-26. doi: 10.1681/ASN.V7122518.
- Background: PubMed 8613533McMillan JI, Riordan JW, Couser WG, Pollock AS, Lovett DH. Characterization of a glomerular epithelial cell metalloproteinase as matrix metalloproteinase-9 with enhanced expression in a model of membranous nephropathy. J Clin Invest. 1996 Feb 15;97(4):1094-101. doi: 10.1172/JCI118502.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Howard A Austin, M.D. principal investigator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus in people with Membranous Glomerulonephritis and Lupus Membranous Nepropathy, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The number of patients who are in 1) complete remission or 2) complete or partial remission. (time frame: 12 months after starting sirolimus). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00050713, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2017.